Process for the preparation of pharmaceutical compositions

ABSTRACT

The invention relates to a process for the preparation of tetracycline derivatives of the formula ##STR1## and acid addition salts thereof --wherein R stands for --CH 3  or ═CH 2  --by dehalogenating and hydrogenating chloromethacycline or acid addition salt thereof of the formula ##STR2## or by hydrating methacycline or acid addition salts thereof of the formula ##STR3## by treatment with hydrogen gas in the presence of a noble metal alloy catalyst on carrier and organic solvent which comprises performing, hydrogenating under pressure of 0.1-1.0 MPa with an alloy catalyst consisting of the alloy palladium or platinum and selenium and/or tellurium used at a ratio of 1:0.01-0.5 related to the amount of the starting tetracycline and carrying out, if desired dehalogenation and hydrogenation in one step.

SPECIFICATION INVENTION

The present invention relates to an improved process for the preparationof doxycycline and methacycline and acid addition salts thereof bycatalytic dehalogenation and hydrogenation by using a tellurium and/orselenium containing alloy catalyst, the latter being prepared accordingto this invention as well.

The following abbreviations are used throughout the specification:

"methacycline":4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methylene-1,11-dioxo-2-naphthacene-carboxamideof the formula ##STR4## "chloro-methacycline":4-dimethylamino-1,4,4a,5,5a,6,11,12-12a-nonahydro-3,5,10,12a-tetrahydroxy-11a-chloro-6-methylene-1,11,12-trioxo-2-naphthacene-carboxamideof the formula ##STR5## "doxycycline":α-6-desoxy-5-hydroxy-tetracycline, i.e.4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12-12a-pentahydroxy-6α-methyl-1,11-dioxo-2-naphthacene-carboxamideof the formula ##STR6## "β-doxycycline" is the β-isomer of doxycycline Rstands for --CH₃ or ═CH₂

BACKGROUND OF THE INVENTION

It is known that methacycline and doxycycline are very effectiverepresentatives of tetracycline type antibiotics.

Several processes are known for the preparation thereof usingoxytetracycline as starting material and preparing chloromethacyclinefollowed by dehalogenation and if desired by hydrogenation the obtainedmethacycline to doxycycline.

Dehalogenation was accomplished--among other methods--by introducinghydrogen gas in the presence of a catalyst, see e.g. Example 9 ofHungarian Patent No. 150909, wherein rhodium precipitated on activecarbon was used.

This process, however, was not satisfactory as reaction products wereproduced which were difficult to separate from by-products and theconversion was not complete either. Therefore the use of secondary ortertiary phosphines has been recommended in Hungarian Patent No. 169605. This process was accompanied with the disadvantage that anequimolar amount of tertiary or secondary phosphines was needed,resulting in a great amount of poisonous waste, and the formed phosphineoxide could be converted again to phosphine only by a multi-stepreaction.

The introduction of hydrogen gas in the presence of a catalyst was alsoused for the saturation of the double bond of the methylene group at the6-position on methacycline in order to produce doxycycline.

In the course of hydrogenation 6-desoxy-5-hydroxy-tetracycline of theformula (IV) can occur in the form of α- and β-isomers. Only theα-isomer is valuable as medicine, i.e. doxycycline. The amount of theα-isomers during hydrogenation determines if the hydrogenation processis successful, i.e. if hydrogenation can be carried out selectively, toproduce mainly α-isomer with a good yield and pure quality.

It is also known that 6-desoxy-5-hydroxy-tetracycline can be preparedwith a yield of 60% by using a 5% palladium or rhodium catalyst on acarrier, but the product was a 1:1 mixture of α- and β-isomers, whichwas followed by the separation of the α-isomer accompanied by furtherlosses (U.S. Pat. No. 3,200,149). The ratio of the formation of theα-isomer can considerably be improved, if the noble metal catalyst on acarrier is poisoned by carbon monoxide, quinoline sulphur or othersulphur compounds. Thus the yield of the α-isomer could be increased to40-50%, but even so the product had to be further purified due to theremaining 10% β-isomer impurities (Hungarian Patent No. 156 925). Inorder to improve the stereoselectivity of hydrogenation an alloycatalyst consisting of the metals of platinum group, copper, silver orgold has been used and a doxycycline yield of about 70% has beendisclosed with 1 to 10% β-isomer impurities (Hungarian Patent No. 167250).

A 92% α-isomer content has been achieved by using a catalyst containingpalladium atoms located on ultra-microporous active carbon, withoutpoisoning, with a yield of 76% (Hungarian Patent No. 169 667).

Hydrogenation could be performed by using Raney nickel and Raney cobaltas a catalyst according to GB-PS No. 1 296 340, but the formation ofα-isomer in the reaction mixtures amounted only to about 40%. Accordingto Finnish Patent No. 67210 to palladium/charcoal catalyst a complex ofbis(diphenylselenide) palladium(II)chloride was added resulting thus ina yield of 75%, wherein the ratio of the α-isomer was about 95%.According to the disclosure this effect could not be achieved ifdiphenylselenide was not used in a complex form.

In order to give a complete review of the known processes, we mentionthose hydrogenation processes, which are not close to our process, butwherein hydrogenation was performed by using triphenyl phosphine rhodiumcomplexes, being catalysts which are soluble in the reaction mixture(DE-OS No. 2 403 714) or by using further additives next to thecomplexes (Hungarian Patent Nos. 169 753, 169 508, 173 508 and 187 465).

Doxycycline could thus be prepared with a good yield and selectivity.

Inspite of the significant development the known processes show manydrawbacks. As already mentioned the use of the known heterogeneouscatalysts only partially solves the problem of stereoselectivity. Aconsiderable amount of these catalysts had to be used, and so the ratiosubstrate-catalyst was not favorable. The relative great amount of theused solvent was also unfavorable. Although the catalysts can be removedfrom the reaction mixture by filtration, the solvent has to be recoveredbefore use by a costly and inefficient procedure.

In the case of homogenous catalysis the catalyst is in solution and itsisolation is not easy. Rhodium is very expensive, it is difficult toobtain, its recovery is complicated, expensive and it can contaminatethe product.

According to the present invention methacycline and doxycycline areprepared in a heterogeneous layer, wherein dehalogenation can beperformed with good yield and reduction takes place stereoselectivetlyand the side reactions can be eliminated to such extent that no extrapurification of the product is needed and the used catalyst can beprepared simply and the specific costs of the catalyst are low.Dehalogenation and hydrogenation can be effected without any extraequipment by using the same type of catalyst. Thus the needed medicinecan be prepared.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation oftetracycline derivatives and acid addition salts thereof of the formula(I) ##STR7## by dehalogenating and hydrogenation chloromethacycline oracid addition salt thereof of the formula II or by hydrogenationmethacycline or acid addition salt thereof of the formula III by atreatment of thereof with hydrogen gas in the presence of a noble metalalloy catalyst on a carrier in the presence of an organic solventcomprising carrying out the hydrogenation at a pressure of 0.1-1.0 MPawith an alloy catalyst used at a ratio of 1:0.01-0.5 related to thestarting tetracycline derivative consisting of an alloy of palladium orplatinum or selenium and/or tellurium and performing, if desired thedehalogenation and hydrogenation in one step.

As a carrier e.g. active charcoal, silica or aluminum oxide can be used.

In order to prepare the noble metal-containing catalyst one may proceedby treating the aqueous suspension of palladium or platinum on a carrierwith a solution or suspension of organic or inorganic selnium ortellurium compounds and optionally by reducing the obtained compound.Such compounds can be selected from salts, oxides and other derivatives,such as selenious acid, diphenyl selenide etc.

One may use a different method according to which palladium or platinumsalts and selenium or tellurium compounds may be dissolved in acidicwater and a carrier, preferably active charcoal can be added to thecarrier, followed by reduction.

The noble metal content of the catalyst may vary between 1 to 30% byweight, preferably 5 to 10% by weight, the used noble metal can beselected from palladium and platinum and the amount of the alloyingcomponents may vary between 1 to 70% by weight related to the amount ofthe noble metal content.

As a solvent preferably lower alcohols, ketones, N,N-dialkyl amides,water and mixtures thereof may be used. It is not necessary to dissolvethe starting material completely.

According to a preferred method methacycline may be prepared bysaturating chloromethacycline with equimolar hydrogen gas at a pressureof 0.1-0.3 MPa in the presence of an alloy catalyst selected frompalladium-selenium, palladium-tellurium, platinum-selenium andplatinum-tellurium by using the catalyst in an amount of 1:0.01-0.2related to the weight of chloromethacycline, wherein the amount of thealloying components amounts to 20-70% by weight related to the noblemetal content.

Methacycline may be recovered from the reaction mixture by any knownmethod in the form of a base, acid addition salt or complex.

The main advantages of the dehalogenation according to the presentinvention are: dehalogenation can be performed without side reactions,the conversion of methacyclines to 5-12a lactones can be suppressed, thereaction takes place at atmospheric pressure and room temperature withina short time, the catalyst can be prepared simply and it is notpyrophoric or its activity does not weaken under storing or in thecourse of the reaction, thus it can be used several times withoutregeneration, thus the catalyst costs of the process are minimal, andalmost negligible.

In order to obtain doxycycline, methacycline or chloromethacycline or asalt thereof can be treated with hydrogen gas in the presence of analloy catalyst consisting of palladium-selenium, palladium-tellurium,platinum-selenium or platinum-tellurium at a pressure of 0.1-1.0 MPawith an amount of catalyst of 1:0.05-0.5, preferably 0.15-0.25 relatedto the weight of methacycline, the amount of the alloying components is1 to 40% by weight.

If chloromethacycline or salts thereof are used as starting materialthen dehalogenation and the selective saturation of the double bond canbe performed in one single step. As a solvent lower alcohol, ketones,dimethylformamide, water and mixtures thereof are used.

When the reaction is terminated the catalyst is filtered and may be usedfor further reactions. The product may be isolated from the filtrate byany known method, such as in the form of a salt of hydrogen halogenicacid, 5-sulfo salicylic acid or in the form of hyclates.

The main advantages of the process for the preparation of doxycyclineare as follows:

the saturation of the exocyclic methylene bond in methacycline takesplace substantially stereoselectively, i.e. the β-isomer content isreduced in doxycycline below 1% by weight (according to HPLC),

in the reactions starting with chloromethacycline dehalogenation andhydrogenation can be carried out in one single technological step, thereaction can be performed at atmospheric pressure and room temperaturewithin a short time,

the catalyst can be rapidly prepared simply, it is not pyrophoric, andits activity does not decrease under storing or in the course of thehydrogenation reaction and thus the catalyst costs of the process areminimal, almost negligible,

the process may be continuous,

the isomerization side reactions occurring in heterogeneous catalyticalreactions, causing intensive decomposition are suppressed and thereforedoxycycline can be obtained with good yield. This experience is highlysurprising as the selenium is known to act as a catalyst in oxidationand isomerization reactions.

Further details of the invention can be found in the following Examples:

EXAMPLE 1

10 g of 10% by weight palladium/charcoal catalyst are suspended in 100ml of water and 0.1 to 0.7 g of selenious acid are added as desired andthe mixture is subjected to hydrogenation at room temperature understirring. The mixture is then filtered, washed with water and acetoneand dried. The activity of the catalyst is measured.

EXAMPLE 2

1.33 g of palladium(II)chloride and 0.2-0.7 g of tellurium(IV)oxide aredissolved in 100 ml of 6N hydrochloric acid, whereafter 10 g of charcoalare added and the mixture is stirred for 3 hours and hydrogenated withhydrogen gas. The catalyst is filtered, washed to neutral and dried. Itsactivity is measured.

EXAMPLE 3

5 g of 10% by weight palladium/charcoal catalyst are suspended in 50 mlof ethanol, and as desired 0.15-1 g of diphenyl selenide are added, thesuspension is boiled for 30 minutes, the catalyst is filtered and dried.Its activity is measured.

EXAMPLE 4

10 g of 5% by weight palladium/silica catalyst are suspended in 100 mlof water and as desired 0.1-0.4 g of selenious acid are added and wefurther proceed as given in Example 1. The activity is measured.

EXAMPLE 5

10 g of 5% by weight platinum/active charcoal catalyst are suspended in100 ml of water and as desired 0.05 g to 0.4 g of selenious acid areadded and we further proceed as disclosed in Example 1.

EXAMPLE 6

1.77 g of palladium(II)chloride and as desired 0.1-0.75 g of seleniumdioxide are dissolved in 80 ml of 12N hydrochloric acid and 5 g ofsilicagel are added, the mixture is hydrogenated, filtered and dried.Its activity is measured.

The activity of the catalysts prepared according to the above Examplesare qualified by a method known per se, by hydrogenating a cyclohexenemodel compound.

PREPARATION OF METHACYCLINE EXAMPLES 7 TO 12

20 g of 11a-chloro-methacycline-p-toluene-sulfonate are reacted withhydrogen gas in 200 ml of solvent by using 1-3 g alloy on a catalystcarrier at room temperature at a pressure of 0.1-0.3 MPa. When theequimolar amount of hydrogen is taken up, the catalyst is filtered off,and working up may be performed as desired as follows:

(a) 20 g of 5-sulfosalicylic acid are added, it is crystallized andmethacycline sulfosalicylate is isolated, or

(b) the filtrate is evaporated in vacuo, and 75 ml of methanol and 7.5 gof p-toluene sulfonic acid are added to the residue. The mixture iscrystallized and methacycline tosylate is isolated, or

(c) the filtrate is evaporated in vacuo and 50 ml concentratedhydrochloric acid are added and methacycline hydrochloride is isolated.Yield: 85-95%.

The quality of the products is thin layer chromatographicallyhomogeneous (developing agent: a 95:5 mixture of tetrahydrofuran andwater) on a silicagel carrier plate impregnated with a buffer of pH=6.Active ingredient content by biological value testing: 100%.

The details are shown in Table I.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                            Catalyst.sup.+       Working up                                          No.  pressure    Solvent.sup.++                                                                         method Product   Yield                              __________________________________________________________________________     7   1 g 5% Pd/charcoal                                                                        methanol-                                                                              (a)    20 g methacycline-                                                                      95.6%                                   Se 20%, 0.1 MPa                                                                           water 3:1       sulfosalicylate                               8   1 g 5% Pt/charcoal                                                                        acetone- (a)    18.8 g methacycline-                                                                    90.0%                                   Se 25%, 0.2 MPa                                                                           water 4:1       sulfosalicylate                               9   2 g 10% Pd/charcoal                                                                       methyl-ethyl-                                                                          (b)    17.9 g methacycline                                                                     95.6%                                   Se 40%, 0.3 MPa                                                                           ketone/water 4:1                                                                              tosylate                                     10   2 g 3.5% Pd/charcoal                                                                      methyl-ethyl-                                                                          (b)    16.4 g methacycline                                                                     88.0%                                   Te 50%, 0.3 MPa                                                                           ketone/water 4:1                                                                              tosylate                                     11   2 g 5% Pd/silicagel                                                                       acetone- (c)    12.45 g methacycline                                                                    87.0%                                   Se 30%, 0.3 MPa                                                                           water 4:1       hydrochloride                                12   1.5 g 10% Pd/charcoal                                                                     acetone- (c)    12.2 g methacycline                                                                     85.0%                                   Se 30%, 0.2 MPa                                                                           water 4:1       hydrochloride                                __________________________________________________________________________     .sup.+ The noble metal content of the catalyst related to the weight of       catalyst is given in % by weight and the amount of the alloying metal is      determined in % by weight related to the noble metal content.                 .sup.++ The composition of the solvent is given in % by volume.          

PREPARATION OF DOXYCYCLINE EXAMPLES 13 TO 20

47.3 g of methacycline hydrochloride or 63.6 g of methacycline p-toluenesulfonate are hydrogenated in 500-580 ml of solvent by using 3.5 to 10 gof an alloy catalyst on carrier at room temperature and a pressure of0.1 to 1.0 MPa until the hydrogen uptake is completed. After filteringoff the catalyst the filtrate can be worked up as follows:

(a) 50 g of 5-sulfosalicylic acid are added to the filtrate and theproduct is crystallized and filtered, dried. Doxycycline sulfosalicylateis obtained as a product, or

(b) the filtrate is evaporated in vacuo, 250 ml methanol and 25 g ofp-toluene sulfonic acid are added to the residue, the mixture iscrystallized and doxycycline tosylate is isolated, or

(c) the filtrate is evaporated in vacuo, 180 ml of ethanol and 30 ml ofhydrochloric acid are added to the residue and after dissolving andclarification 50 ml of hydrochloric acid and ethanol in hydrochloricacid are added to the filtrate. The mixture is crystallized anddoxycycline hyclate is isolated, or

(d) the filtrate is evaporated to dryness in vacuo, 250 ml of acetoneare added to the residue and by introducing hydrochloric acid gas thedoxycycline hydrochloride is recovered.

Yield: 80-90%. Quality of the product is homogeneous according to thinlayer chromatography.

Active ingredient content by biological value testing: 100%.

Ratio of α-isomer: 99%, ratio of β-isomer: 0-0.6%.

The details are shown in Table II.

                                      TABLE II                                    __________________________________________________________________________    Example                                                                            Catalyst.sup.+       Working up                                          No.  pressure    Solvent.sup.++                                                                         method Product   Yield                              __________________________________________________________________________    13   10 g 5% Pd/charcoal                                                                       acetone  (a)    62 g doxycycline-                                                                       89%                                     Se 5%, 0.3 MPa                                                                            water 4:1       sulfosalicylate                              14   5 g 5% Pt/charcoal                                                                        methyl-ethyl-                                                                          (a)    61.5 g doxycycline-                                                                     88%                                     Se 8%, 0.3 MPa                                                                            ketone/water 4:1                                                                              sulfosalicylate                              15   8 g 10% Pd/charcoal                                                                       acetone- (b)    54.1 g doxycycline-                                                                     88%                                     Se 20%, 0.4 MPa                                                                           water 4:1       tosylate                                     16   5 g 3.5% Pd/charcoal                                                                      methyl-ethyl-                                                                          (b)    50.5 g doxycycline-                                                                     82%                                     Te 15%, 0.5 MPa                                                                           ketone/water 4:1                                                                              tosylate                                     17   10 g 5% Pd/silicagel                                                                      methyl-ethyl-                                                                          (c)    43.1 g doxycycline-                                                                     85%                                     Se 10%, 0.3 MPa                                                                           ketone/water 4:1                                                                              hyclate                                      18   4 g 10% Pd/charcoal                                                                       acetone- (c)    42.6 g doxycycline-                                                                     83%                                     Se 15%, 0.3 MPa                                                                           water 4:1       hyclate                                      19   6 g 10% Pd/charcoal                                                                       acetone- (d)    40.6 g doxycycline-                                                                     88%                                     Se 12%, 0.2 MPa                                                                           water 4:1       hydrochloride                                20   10 g 5% Pd/silicagel                                                                      methyl-ethyl-                                                                          (d)    39.2 g doxycycline-                                                                     85%                                     Se 7%, 0.3 MPa                                                                            ketone/water 4:1                                                                              hydrochloride                                __________________________________________________________________________     .sup.+ The nobel metal content of the catalyst related to the weight of       catalyst is given in % by weight and the amount of the alloying metal is      determined in % by weight related to the noble metal content.                 .sup.++ The composition of the solvent is given in % by volume.          

EXAMPLES 21-28

66.7 g of 11a-chloro-methacycline-p-toluene-sulfonate are subjected tohydrogenation in 500-580 ml of solvent by using 3.5 to 10 g of an alloycatalyst on carrier at room temperature and a pressure of 0.1 to 1.0 MPauntil the hydrogen uptake is completed. After filtering off the catalystthe filtrate can be worked up as follows:

(a) 50 g of 5-sulfosalicylic acid are added to the filtrate and theproduct is crystallized and filtered, dried. Doxycycline sulfosalicylateis obtained as a product, or

(b) the filtrate is evaporated in vacuo, 250 ml methanol and 25 g ofp-toluene sulfonic acid are added to the residue, the mixture iscrystallized and doxycycline tosylate is isolated, or

(c) the filtrate is evaporated in vacuo, 180 ml of ethanol and 30 ml ofhydrochloric acid are added to the residue and after dissolving andclarification 50 ml of hydrochloric acid and ethanol in hydrochloricacid are added to the filtrate. The mixture is crystallized anddoxycycline hyclate is isolated, or

(d) the filtrate is evaporated to dryness in vacuo, 250 ml of acetoneare added to the residue and by introducing hydrochloric acid gas thedoxycycline hydrochloride is recovered.

Yield: 80-90%. Quality of the product is homogeneous according to thinlayer chromatography.

Active ingredient content by biological value testing: 100%.

Ratio of α-isomer: 99%, ratio of β-isomer: 0-0.6%.

The details are shown in Table III.

                                      TABLE III                                   __________________________________________________________________________    Example                  Pressure                                                                           Working up                                      No.  Catalyst.sup.+                                                                           Solvent.sup.++                                                                         MPa  method Product   Yield                          __________________________________________________________________________    21   10 g 5% Pd/charcoal                                                                      acetone- 0.2-0.4                                                                            a/     61.5 g doxycycline                                                                      88%                                 Se 5%      water 4:1            sulfosalicylate                                                                         88%                            22   5 g 5% Pd/charcoal                                                                       methyl-ethyl-                                                                          0.2-0.4                                                                            a/     59.2 g doxycycline                                                                      85%                                 Se 8%      ketone/water 4:1     sulfosalicylate                          23   8 g 10% Pd/charcoal                                                                      acetone-water                                                                          0.3-0.5                                                                            b/     53.6 g doxycycline-                                                                     87%                                 Se 20%     4:1                  tosylate                                 24   5 g 3.5% Pd/charcoal                                                                     methyl-ethyl-                                                                          0.4-0.5                                                                            b/     50.5 g doxycycline-                                                                     82%                                 Te 15%     ketone/water 4:1     tosylate                                 25   10 g 5% Pd/silicagel                                                                     methyl-ethyl-                                                                          0.2-0.4                                                                            c/     42.1 g doxycycline-                                                                     82%                                 Se 10%     ketone/water 4:1     hyclate                                  26   4 g 10% Pd/charcoal                                                                      acetone- 0.4-0.5                                                                            c/     42.1 g doxycycline-                                                                     82%                                 Se 15%     water 4:1            hyclate                                  27   6 g 10% Pd/charcoal                                                                      acetone- 0.2-0.3                                                                            d/     39.2 g doxycycline-                                                                     85%                                 Se 12%     water 4:1            hydrochloride                            28   10 g 5% Pd/silicagel                                                                     methyl-ethyl-                                                                          0.2-0.3                                                                            d/     38.3 g doxycycline-                                                                     83%                                 Se 7%      ketone/water 4:1     hydrochloride                            __________________________________________________________________________     .sup.+ The nobel metal content of the catalyst related to the weight of       catalyst is given in % by weight and the amount of the alloying metal is      determined in % by weight related to the nobel metal content.                 .sup.++ The composition of the solvent is given in % by volume.          

We claim:
 1. Process for the preparation of tetracycline derivatives ofthe formula ##STR8## and acid addition salts thereof wherein R standsfor --CH₃ by dehalogenating and hydrogenating chloromethacycline or acidaddition salts thereof of the formula ##STR9## or by hydrogenatingmethacycline or acid addition salts thereof of the formula ##STR10## bya treatment with hydrogen gas in the presence of a noble metal alloycatalyst on a carrier and an organic solvent which comprises performinghydrogenating under pressure of 0.1-1.0 MPa with an alloy catalystconsisting of either palladium or platinum and selenium, tellurium or amixture thereof used at a ratio of 1:0.01-0.5 related to the amount ofthe starting tetracycline and carrying out, if desired dehalogenationand hydrogenation in one step.
 2. Process as claimed in claim 1 whichcomprises preparing methacycline by saturating chloromethacycline withequimolar hydrogen gas in the presence of an alloy catalyst ofpalladium-selenium, palladium-tellurium or platinum-selenium orplatinum-tellurium on a carrier under a pressure of 0.1-0.3 MPa at aratio of 1:0.01-0.2 catalyst related to the amount ofchloromethacycline, wherein the amount of selenium, tellurium or amixture thereof amounts to 20-70% by weight related to the amount ofpalladium or platinum.
 3. Process as claimed in claim 1 which comprisespreparing doxycycline by treating methacycline or salts thereof withhydrogen gas in the presence of an alloy catalyst consisting ofpalladium-selenium, palladium-tellurium, platinum-selenium orplatinum-tellurium on a carrier at a pressure of 0.1-1 MPa at a ratio of1:0.05-5 catalyst related to the weight of methacycline, wherein theamount of the alloying components amounts to 1-40% by weight.
 4. Processas claimed in claim 1 which comprises preparing doxycycline by treatingchloromethacycline or salts thereof with hydrogen gas in the presence ofan alloy catalyst consisting of palladium-selenium, palladium-tellurium,platinum-selenium or platinum-tellurium on a carrier at a pressure of0.1-1 MPa at a ratio of 1:0.05-5 catalyst related to the weight ofmethacycline, wherein the amount of the alloying components amounts to1-40% by weight.
 5. Process as claimed in claim 2 which comprises usingwater, alcohols, ketones or mixtures thereof as a solvent.
 6. Process asclaimed in claim 1 which comprises using as alloys for hydrogenationalloys which contain 1-70% by weight of selenium or tellurium and 99-30%by weight of palladium or platinum.